Apparatus and method for blood oxygenation

ABSTRACT

An apparatus for blood oxygenation and delivery is provided. The apparatus advantageously comprises a liquid-to-liquid oxygenation assembly with a pressurizable chamber having inlets for a first gas-supersaturated fluid and a second fluid, such as blood. The inlets are advantageously positioned on the mixing chamber in such a way that the first fluid and the second fluid enter the mixing chamber normally to each other to promote mixing and liquid-to-liquid gas transfer. The apparatus also includes a delivery system coupled to the blood oxygenation assembly. The delivery system includes a generally tubular elongated member having a proximal end portion, a distal end portion, and a transition portion located between the proximal end portion and the distal end portion. The transitional portion is relatively flexible compared to the proximal end portion and is relatively stiff compared to the distal end portion. In another embodiment, the delivery system includes a generally tubular elongated member having a proximal end portion and a distal end portion with a plurality of holes.

FIELD OF THE INVENTION

The present invention relates generally to a system and method foroxygenating blood, and more particularly, to a system and method forproviding oxygenated blood, e.g., hyperoxemic or hyperbaric blood, to apatient.

BACKGROUND OF THE INVENTION

Oxygen is a crucial nutrient for human cells. Cell damage may resultfrom oxygen deprivation for even brief periods of time, which may leadto organ dysfunction or failure. For example, heart attack and strokevictims experience blood flow obstructions or diversions that preventoxygen from being delivered to the cells of vital tissues. Withoutoxygen, the heart and brain progressively deteriorate. In severe casesdeath results from complete organ failure. Less severe cases typicallyinvolve costly hospitalization, specialized treatments and lengthyrehabilitation.

Blood oxygen levels may be described in terms of the concentration ofoxygen that would be achieved in a saturated solution at a given partialpressure of oxygen (pO₂). Typically, for arterial blood, normal bloodoxygen levels (i.e., normoxia or normoxemia) range from 90-110 mm Hg.Hypoxemic blood (i.e., hypoxemia) is arterial blood with a pO₂ less than90 mm Hg. Hyperoxic blood (i.e., hyperoxemia or hyperoxia) is arterialblood with a pO₂ greater than 400 mm Hg (see Cason et. al (1992) Effectsof High Arterial Oxygen Tension on Function, Blood Flow Distribution,and Metabolism in Ischemic Myocardium, Circulation, 85(2):828-38, butless than 760 mm Hg (see Shandling et al. (1997) Hyperbaric Oxygen andThrombolysis in Myocardial Infarction: The “HOT MI” Pilot Study,American Heart Journal 134(3):544-50). Hyperbaric blood is arterialblood with a pO₂ greater than 760 mm Hg. Venous blood typically has apO₂ level less than 90 mm Hg. In the average adult, for example, normalvenous blood oxygen levels range generally from 40 mm Hg to 70 mm Hg.

Blood oxygen levels also might be described in terms of hemoglobinsaturation levels. For normal arterial blood, hemoglobin saturation isabout 97% and varies only slightly as pO₂ levels increase. For normalvenous blood, hemoglobin saturation is about 75%

In patients who suffer from acute myocardial infarction, if themyocardium is deprived of adequate levels of oxygenated blood for aprolonged period of time, irreversible damage to the heart can result.Where the infarction is manifested in a heart attack, the coronaryarteries fail to provide adequate blood flow to the heart muscle.

Treatment of acute myocardial infarction or myocardial ischemia oftencomprises performing angioplasty or stenting of the vessels to compress,ablate or otherwise treat the occlusion(s) within the vessel walls. Forexample, a successful angioplasty uses a balloon to increase the size ofthe vessel opening to allow increased blood flow.

Even with the successful treatment of occluded vessels, a risk of tissueinjury may still exist. During percutaneous transluminal coronaryangioplasty (PTCA), the balloon inflation time is limited by thepatient's tolerance to ischemia caused by the temporary blockage ofblood flow through a vessel during balloon inflation. Reperfusion injuryalso may result, for example, due to slow coronary reflow or no reflowfollowing angioplasty.

For some patients angioplasty procedures are not an attractive optionfor the treatment of vessel blockages. Such patients typically are atincreased risk of ischemia for reasons such as poor left ventricularfunction, lesion type and location, or the amount of the myocardium atrisk. The treatment options for such patients thus include more invasiveprocedures such as coronary bypass surgery.

To reduce the risk of tissue injury typically associated with treatmentsof acute myocardial infarction and myocardial ischemia, it is usuallydesirable to deliver oxygenated blood or oxygen-enriched fluids toat-risk tissues. Tissue injury is minimized or prevented by thediffusion of the dissolved oxygen from the blood or fluids to the tissueand/or blood perfusion that removes metabolites and that provides otherchemical nutrients.

In some cases, the desired treatment of acute myocardial infarction andmyocardial ischemia includes perfusion of oxygenated blood oroxygen-enriched fluids. During PTCA, for example, tolerated ballooninflation time may be increased by the concurrent introduction ofoxygenated blood into the patient's coronary artery. Increased bloodoxygen levels also may cause the normally perfused left ventricularcardiac tissue into hypercontractility to further increase blood flowthrough the treated coronary vessels.

The infusion of oxygenated blood or oxygen-enriched fluids also may becontinued following the completion of PTCA treatment or other procedures(e.g. surgery) wherein cardiac tissue “stunning” with associatedfunction compromise has occurred. In some cases continued infusion mayaccelerate the reversal of ischemia and facilitate recovery ofmyocardial function.

Conventional methods for the delivery of oxygenated blood oroxygen-enriched fluids to at-risk tissues involve the use of bloodoxygenators. Such procedures generally involve withdrawing blood from apatient, circulating it through an oxygenator to increase blood oxygenconcentration, and then delivering the blood back to the patient. Oneexample of a commercially available blood oxygenator is the Maxima bloodoxygenator manufactured by Medtronic, Inc., Minneapolis, Minn.

There are drawbacks, however, to the use of a conventional oxygenator inan extracorporeal circuit for oxygenating blood. Such systems typicallyare costly, complex and difficult to operate. Often a qualifiedperfusionist is required to prepare and monitor the system.

Conventional oxygenator systems also typically have a large primingvolume, i.e., the total volume of blood contained within the oxygenator,tubing and other system components, and associated devices. It is notuncommon in a typical adult patient case for the oxygenation system tohold more than one to two liters of blood. Such large priming volumesare undesirable for many reasons. For example, in some cases a bloodtransfusion may be necessary to compensate for the blood temporarilylost to the oxygenation system because of its large priming volume.Heaters often must be used to maintain the temperature of the blood atan acceptable level as it travels through the extracorporeal circuit.Further, conventional oxygenator systems are relatively difficult toturn on and off. For instance, if the oxygenator is turned off, largestagnant pools of blood in the oxygenator might coagulate.

In addition, with extracorporeal circuits including conventional bloodoxygenators there is a relatively high risk of inflammatory cellreaction and blood coagulation due to the relatively slow blood flowrates and the large blood contact surface area. A blood contact surfacearea of about 1-2 m² and velocity flows of about 3 cm/s are not uncommonwith conventional oxygenator systems. Thus, relatively aggressiveanti-coagulation therapy, such as heparinization, is usually required asan adjunct to using the oxygenator.

Perhaps one of the greatest disadvantages to using conventional bloodoxygenation systems is that the maximum partial pressure of oxygen (pO₂)that can be imparted to blood with commercially available oxygenators isabout 500 mm Hg. Thus, blood pO₂ levels near or above 760 mm Hg cannotbe achieved with conventional oxygenators.

Some experimental studies to treat myocardial infarction have involvedthe use of hyperbaric oxygen therapy. See, e.g., Shandling et al.(1997), Hyperbaric Oxygen and Thrombolysis in Myocardial Infarction: The“HOT MI” Pilot Study, American Heart Journal 134(3):544-50. Thesestudies generally have involved placing patients in chambers of pureoxygen pressurized at up to 2 atmospheres, resulting in systemicoxygenation of patient blood up to a pO₂ level of about 1200 mm Hg.However, use of hyperbaric oxygen therapy following restoration ofcoronary artery patency in the setting of an acute myocardial infarctionis not practical. Monitoring critically ill patients in a hyperbaricoxygen chamber is difficult. Many patients become claustrophobic. Eardamage may occur. Further, treatment times longer than 90 minutes cannotbe provided without concern for pulmonary oxygen toxicity.

For these reasons, the treatment of regional organ ischemia generallyhas not been developed clinically. Thus, there remains a need for asimple and convenient system for delivering oxygenated blood and otherfluids to patients for the localized prevention of ischemia and thetreatment of post-ischemic tissue and organs.

SUMMARY OF THE INVENTION

The present invention may address one or more of the problems set forthabove. Certain possible aspects of the present invention are set forthbelow as examples. It should be understood that these aspects arepresented merely to provide the reader with a brief summary of certainforms the invention might take and that these aspects are not intendedto limit the scope of the invention. Indeed, the invention may encompassa variety of aspects that may not be set forth below.

In one embodiment of the present invention, a system for the preparationand delivery of oxygenated blood is provided. In applications involvingthe prevention of ischemia or the treatment of ischemic tissues, thesystem may be used for the preparation and delivery of oxygenated bloodto a specific location within a patient's body. The system may includean extracorporeal circuit for oxygenating blood, e.g., increasing thelevel of oxygen in the blood, in which the blood to be oxygenated isblood withdrawn from the patient. The system also may be usedadvantageously for regional or localized delivery of oxygenated blood.

Factors influencing the determination of blood flow characteristics forthe extracorporeal circuit may include one or more of the many clinicalparameters or variables of the oxygenated blood to be supplied to thepatient, e.g., the size of the patient, the percentage of overallcirculation to be provided, the size of the target to be accessed,hemolysis, hemodilution, pO₂, pulsatility, mass flow rate, volume flowrate, temperature, hemoglobin concentration and pH.

Interventional Devices (Catheters, Infusion Guidewires, etc.)

The system may comprise a delivery assembly including an elongated,generally tubular assembly including a central lumen and at least oneend placeable within a patient body proximate a tissue site to betreated, the end including an outlet port for the oxygenated blood. Thedelivery assembly advantageously comprises a catheter defining a fluidpathway, including a proximal portion adapted for coupling to anoxygenated blood supply assembly, and a distal portion defining a fluidpathway removably insertable within a patient's body, for infusing theoxygenated blood to predetermined sites. Alternatively, the deliveryassembly may comprise an infusion guidewire, sheath, or other similarinterventional device of the type used to deliver fluids to patients.

The embodiments may be used in conjunction with angiographic or guidingcatheters, arterial sheaths, and/or other devices used in angioplastyand in other interventional cardiovascular procedures. The system may beused in applications involving one or more vascular openings, i.e., ineither contralateral or ipsilateral procedures.

In contralateral procedures blood is withdrawn from the patient at afirst location, e.g., the left femoral artery. The oxygenated blood isreturned to the patient at a second location proximate the tissue to betreated. Blood oxygenation occurs as the blood pumped through theextracorporeal circuit or loop passes through an oxygenation assemblyand forms the oxygenated blood to be delivered. In applications wherethe system includes a catheter, the catheter may include a distal endremovably insertable within a patient's body through a second location,such as the patient's right femoral artery. The distal end includes atleast one port in fluid communication with the central lumen and throughwhich the oxygenated blood may exit. Further, the distal portion of thecatheter may be adapted with a tip portion shaped so as to promoteinsertion of the device, such as through the same sheath used forinterventional procedures like angioplasty, to specific predeterminedlocations within a patient's body. Examples of tip portion shapes whichmay be used include any of the standard clinically accepted tipconfigurations used with devices like guide catheters for providingaccess to and for holding in locations like the coronary ostium.Accordingly, the method may further include the step of positioning theportion of the distal end of the catheter including the fluid exit portat a predetermined location within a patient body proximate to thetissue to be treated.

In ipsilateral procedures, the system may be used along with one or moreof any of a number of suitable, standard-size, clinically accepted guidecatheters and/or introducer sheaths. The system, for example, maycomprise a catheter, a catheter and guide catheter, or a catheter andsheath, for use within a guide catheter or introducer sheath used forthe primary interventional procedure.

The delivery assembly advantageously comprises a catheter suitable forsub-selective delivery of the oxygenated blood. However, the catheterembodiment selected for use will depend upon the circumstances involvedin a particular application. For example, in some cases involving theprevention of myocardial ischemia or the treatment of ischemicmyocardial tissues, a selective or non-selective catheter may bepreferred.

The delivery of oxygenated blood may occur via a “simple” interventionaldevice (e.g., a catheter or infusion guidewire) or a delivery device orlumen associated with or forming a part of a multiple-component assemblyoperable for the performance of diagnostic and/or therapeutic procedures(i.e., in addition to the delivery of oxygenated blood). Examples ofsuch assemblies include, without limitation, devices for the placementof stents, angioplasty balloon catheters, radiation delivery systems,drug delivery devices, etc. Flow rates of about 25 ml/min to about 200ml/min for the oxygenated blood may be advantageous, particularly about75 ml/min to about 125 ml/min.

Fluid Delivery Pathways

Advantageously, oxygenated blood is provided to a particular desiredlocation by a fluid delivery apparatus including: (1) a generallyelongated fluid delivery assembly having a proximal section and a distalsection, the distal section including a portion at least partiallyremovably insertable within a patient's body, the removably insertableportion including at least one fluid exit port in fluid communicationwith a fluid delivery lumen extending between the proximal section andthe removably insertable portion of the fluid delivery assembly; and (2)a fluid conduit having: a first end portion for receiving a supply ofblood at the outlet of a blood pump operably coupled to the fluidconduit; a second end releasably coupled to the fluid delivery lumen ofthe fluid delivery assembly; and an intermediate portion between thefirst and second ends adapted for oxygenating the supply of blood; thefluid conduit and the fluid delivery lumen defining a continuous fluidpathway between the first end portion of the fluid conduit and the fluidexit port(s). Advantageously, the fluid delivery apparatus providesoxygenated blood, and most advantageously hyperoxemic or hyperbaricblood, to a patient without potentially clinically significant gasbubbles in the blood. More advantageously, the fluid delivery apparatuscan provide to a patient oxygenated blood having a pO₂ greater thanabout 760 mm Hg but less than pO_(2max) for a given blood flow rateQ_(blood), where pO_(2max) equals the maximum back pressure generatedwithin the fluid delivery apparatus by operation of the blood pump toachieve the flow rate Q_(blood).

In one embodiment, the intermediate portion of the fluid conduit adaptedfor oxygenating the blood supplied by the blood pump, i.e., theoxygenation assembly, comprises a high pressure membrane oxygenator. Inanother embodiment, the fluid conduit intermediate portion comprises anassembly including a mixing region in which an oxygenated fluid, e.g.,an oxygen-supersaturated fluid, combines with the blood to effect directliquid-to-liquid oxygenation. In a further embodiment, the intermediateportion may comprise an assembly for combining two fluid streams (e.g.,an apparatus generally resembling a y-tube, t-adaptor, or the like), theassembly adapted for coupling to delivery systems for supplying blood tobe oxygenated and for supplying oxygenated blood or other fluids.

Accordingly, the fluid delivery apparatus advantageously may comprise afirst tube portion extending between a blood pump and an oxygenationassembly; the oxygenation assembly; a second tube portion extendingbetween the oxygenation assembly and the proximal end of a fluiddelivery assembly; and the fluid delivery assembly.

In a patient breathing air through the lungs, the dissolved gases in thepatient's blood (nitrogen, N2; carbon dioxide, CO2; and oxygen, O2)equal atmospheric pressure. Chemically, this relationship is noted bythe equation

P _(total) =pN₂ +pCO₂ +pO₂

where P_(total) is atmospheric pressure and the right-hand side of theequation shows the relative, or partial, pressures of the dissolvedgases in air. The above equation is balanced approximately as follows:

760 mm Hg=600 mm Hg+45 mm Hg+115 mm Hg

For P_(blood) including dissolved gases having the partial pressures putforth above, during a hyperoxygenation process occurring at theintermediate portion of the fluid conduit the pO₂ is raised andP_(total) can exceed atmospheric pressure. For example, if the pO₂increases to 800 mm Hg without change to pN2 and pCO2, then P_(total)would equal 1445 mm Hg, a nearly two-fold increase.

The fluid pressure at the outlet of the intermediate portion of thefluid conduit, P_(fluid), is a measure of the pressure differentialacross the portion of the fluid conduit between that location and thefluid exit port(s) plus the outlet pressure. To avoid the formation ofpotentially clinically significant gas bubbles, it is particularlyadvantageous to raise the fluid pressure at the outlet of theintermediate portion of the fluid conduit to a level that exceeds thetotal dissolved gas pressure. Thus, delivery of oxygenated blood mayoccur bubble-free, i.e., without the formation of potentially clinicallysignificant bubbles, where P_(fluid)>P_(total).

Because most pressure measurements use gauge pressures (i.e., gaugepressure=total pressure minus atmospheric pressure), the relationshipfor bubble-free delivery also may be simplified and approximated toΔP_(fluid)>pO_(2(out)), where pO_(2(out)) is the pO₂ of the oxygenatedblood to be delivered to the patient. In other words, a caregiver mightneed only compare two simple measurements, ΔP_(fluid) and pO_(2(out)),to ensure bubble-free delivery during a procedure.

Experimental data supports use of the simplified and approximatedrelationship ΔP_(fluid)>pO_(2(out)) for achieving bubble-free delivery.As shown in Table I, a fluid delivery apparatus including aliquid-to-liquid oxygenation assembly was used with two catheters havingdifferent effective diameters to infuse oxygenated blood into the leftcoronary vasculature of a 40 kg swine to determine whether therelationship between ΔP_(fluid) and pO_(2(out)) affects bubble formationduring oxygenated blood infusion. In trials whereΔP_(fluid)>pO_(2(Out)), no bubbles were observed using2D-echocardiography during oxygenated blood infusion, and an ultrasonicbubble detection system did not detect any bubbles of greater than about100 μm diameter. On the other hand, in trials whereΔP_(fluid)<pO_(2(out)), 3-4 bubbles per heart beat were observed in theright atrium using 2D-echocardiography during oxygenated blood infusion,and the ultrasonic bubble detection system numerous bubbles of greaterthan about 100 μm diameter.

TABLE I Blood/Oxygenated Ultra- Fluid sonic Bubbles in Blood(dimensionless Bubble 2D-Echo Flow fluid flow Event (#/ (ml/min) rateratio) ΔP_(fluid) pO_(2(out)) (#) heart beat) 78 52 843 783 0 0 78 52819 723 0 0 103 47 1043 834 0 0 104 35 1031 982 0 0 107 36 311 987 323-4 107 36 315 1031 15 3-4 152 51 449 771 24 3-4 152 51 460 741 69 3-4

Typically, pO_(2(out)) may be selected by the caregiver based upon thecircumstances involved in a particular application. Thus, bubble-freedelivery may be ensured by selecting an appopriate fluid deliveryapparatus, i.e., one which may effect downstream of the fluid conduitintermediate portion a fluid pressure drop that exceeds the selectedtarget pO₂ for a given blood flow rate. Further, the fluid pressure dropmay vary depending upon factors such as fluid delivery length and fluidlumen geometry (e.g., internal diameter, taper, cross-sectional profile,etc.), factors which may vary depending upon the specific applicationinvolved. Thus, it may prove helpful (e.g., to promote ease ofselection) to characterize all or a portion of the fluid deliveryapparatus downstream of the intermediate portion of the fluid conduit interms of an effective diameter, or in terms of achievable pO₂ levels fora given oxygenation assembly and/or give conditions at the outlet of theintermediate portion of the fluid conduit.

For example, in accordance with one embodiment of the present invention,for an exemplary oxygenated blood fluid delivery apparatus, oxygenatedblood pressure at the oxygenation assembly is a function of blood flowrate and catheter effective diameter. For an oxygenated blood fluiddelivery apparatus, the relationship between blood flow rate andoxygenated blood pressure at the oxygenation assembly for a givencatheter may be determined using the Hagen-Poiseuille law:$Q = \frac{\pi \quad \Delta \quad P\quad D^{4}}{128\quad L\quad \eta}$

which generally governs laminar fluid flows through conduits, in whichQ=volumetric flow rate; L=conduit length; D=conduit inside diameter;η=fluid viscosity; and ΔP=pressure difference across the conduit length.Other embodiments also may be used depending upon the circumstancesinvolved in a particular application, e.g., an embodiment for turbulentflow applications, for which the relationship between blood flow rateand oxygenated blood pressure at the oxygenation assembly may bedetermined using models governing turbulent flow.

In general, with a given oxygenated blood fluid delivery apparatus, fora constant blood flow rate Q_(blood), as the effective inner diameter ofthe catheter increases, the blood pressure P_(fluid(gauge)) at theoxygenation assembly decreases. By knowing the simplified andapproximated bubble-free delivery relationship, ΔP_(fluid)>pO_(2(out)),a caregiver having a catheter characterized by effective inner diametermay determine whether an appropriate range of blood flow rates areachievable if the caregiver were to use a fluid delivery apparatusincluding the catheter to deliver blood having a desired pO₂.Alternatively, a caregiver specifying a desired oxygenated blood pO₂ andoxygenated blood flow rate range may select a catheter for use in afluid delivery apparatus for a particular application.

High Pressure Membrane Oxygenation Assemblies

In one embodiment, the system provided advantageously includes amembrane oxygenator assembly and assemblies for supplying controlledflows or supplies of oxygen gas and blood. Advantageously, theintermediate portion of the fluid conduit comprises a membraneoxygenator assembly operable at high pressures, i.e., oxygen gas andblood supply pressures within the membrane oxygenator assembly ofgreater than atmospheric pressure.

The assembly for supplying controlled flows or supplies of oxygen gasadvantageously includes a regulated source of oxygen gas, so that oxygengas is delivered to the membrane oxygenator assembly at a pressuregreater than atmospheric pressure. Advantageously, oxygen gas issupplied to the membrane oxygenator assembly at a pressure greater thanatmospheric pressure and less than about 50 p.s.i.a., the approximatemaximum pressure that may be generated by commercially available bloodpumps delivering blood. The assembly for supplying controlled flows orsupplies of oxygen gas may be one of the many commercially available andclinically accepted oxygen delivery systems suitable for use with humanpatients (e.g., regulated bottled oxygen).

The assembly for supplying controlled flows or supplies of bloodadvantageously includes a source of blood in combination with means forproviding the blood to the membrane oxygenator assembly. Advantageously,the blood to be oxygenated comprises blood withdrawn from the patient,so that the blood supply assembly includes a blood inlet disposed alonga portion of a catheter or other similar device at least partiallyremovably insertable within the patient's body; a pump loop that incombination with the catheter or other device defines a continuous fluidpathway between the blood inlet and the membrane oxygenator assembly;and a blood pump for controlling the flow of blood through the pumploop, i.e., the flow of blood provided to the membrane oxygenatorassembly. The blood pump may be one of the many commercially availableand clinically accepted blood pumps suitable for use with humanpatients. One example of such a pump is the Model 6501 RFL3.5 Pemcoperistaltic pump available from Pemco Medical, Cleveland, Ohio.

The system provided advantageously includes an oxygenated blood supplyassembly comprising a membrane oxygenator assembly including at leastone membrane separating within the membrane oxygenator assembly theoxygen gas provided by the oxygen gas supply assembly and the bloodprovided by the blood supply assembly, and across which oxygen and othergases may diffuse. Advantageously, oxygen gas is provided to the “gasside” of the membrane oxygenator assembly by the oxygen gas supplyassembly at a gas side pressure that is greater than atmosphericpressure; a supply of blood is provided by the blood supply assembly tothe “blood side” of the membrane oxygenator assembly at a blood sidepressure that is greater than the gas side pressure; and the oxygen gasand at least a portion of the supply of blood is maintained in contactwith the membrane so that oxygen diffuses across the membrane anddissolves in the supply of blood.

The membrane may comprise either a solid material (e.g., siliconerubber) or a microporous material (e.g., a polymeric material, such aspolypropylene). Advantageously, the blood side pressure is maintained ata higher level than the gas side pressure to prevent bulk gas flowacross the membrane. However, lower blood side pressures may be used ifa solid, non-porous membrane is used. The type of membrane used, and thegas and blood side pressures (which may be defined, for example, by agiven pressure differential across the membrane) may vary depending uponthe circumstances involved in a particular desired application.

The gas side of the membrane oxygenator assembly may be operated ineither an “open” or a “closed” mode. In open mode, a gas side streamincluding oxygen gas provided by the oxygen gas supply assembly “sweeps”through the gas side of the membrane oxygenator assembly. During thesweep oxygen diffuses across the membrane to dissolve in the blood, andblood gases such as carbon dioxide and nitrogen may diffuse across themembrane to join the gas side stream. The gas side stream exits themembrane oxygenator assembly via a vent or other fluid exit conduit. Inclosed mode, the vent or other fluid exit conduit is closed so as toprevent the escape of bulk gas from the gas side of the membraneoxygenator assembly.

In an alternate embodiment, the membrane oxygenator assembly includes agas inlet but is not adapted with a vent or other gas side stream fluidexit conduit. This alternate embodiment thus comprises a closed modedevice. In closed mode operation the gas side pressure advantageouslyequals the pressure at which the oxygen gas supply assembly providesoxygen gas to the membrane oxygenator assembly. In open mode the gasside pressure drops through the membrane oxygenator assembly, albeitperhaps only slightly, from the pressure at which the oxygen gas supplyassembly provides oxygen gas to the membrane oxygenator assembly.

The membrane oxygenator assembly advantageously is sized depending uponthe circumstances involved in a particular desired application. Forexample, for an oxygenated blood delivery flow less than 0.3 liters perminute, an active membrane surface area of much less than two squaremeters (the approximate active membrane surface area for a conventionaladult size oxygenator capable of handling six liters of blood perminute) is required. By way of example only, and without limitation onthe scope of the present invention, factors affecting membraneoxygenator assembly sizing include the desired oxygen level for theblood to be oxygenated and oxygenated blood flow rate.

The system provided advantageously delivers oxygenated blood from themembrane oxygenator assembly to a given site without the formation orrelease of clinically significant oxygen bubbles. Delivery of oxygenatedblood at a given site without clinically significant bubble formation orrelease advantageously may be accomplished through the selection of acatheter material, the use of an appropriately sized delivery catheter,and/or the conditioning of the same to eliminate nucleation sites. Theexact material, size and conditioning procedure may vary depending uponthe circumstances involved in a particular application. By way ofexample only, and without limitation as to the scope of the presentinvention, for the delivery of about 3 ml/sec of oxygenated blood with amembrane oxygenator assembly operating with a gas side pressure of about50 p.s.i., a catheter having a length of about 130 cm and insidediameter of about 40 mils would provide a gradual pressure reductionwhich may help prevent the release of potentially clinically significantgas bubbles.

In another embodiment, a method is provided for the preparation anddelivery of oxygenated blood. A method for enriching blood with oxygenis provided comprising providing a membrane having first and secondsides; providing in contact with the first side of the membrane oxygengas at a pressure P1 that is greater than atmospheric pressure;providing on the second side of the membrane a supply of blood at apressure P2 that is greater than P1; and maintaining at least a portionof the supply of blood in contact with the second side of the membraneso that oxygen diffuises across the membrane and dissolves in the supplyof blood. Advantageously, the pressure P1 is greater than atmosphericpressure and less than about 50 p.s.i.a. The method advantageouslyfurther comprises providing in contact with the first side of themembrane a stream including oxygen gas. Advantageously, the streammaintains contact with the first side of the membrane so that a gas(e.g., carbon dioxide, nitrogen, water vapor, etc.) in the supply ofblood diffuses across the membrane and joins the stream.

In accordance with another embodiment, a method is provided fordelivering oxygenated blood to a specific site within a patient's body.The method comprises raising the pO₂ level of blood to be supplied tothe patient and the delivery of such blood to a given site. The methodmay include the step of controlling or providing controlled amounts ofblood and oxygen gas to a membrane oxygenator assembly so as to produceoxygenated blood for delivery to a specific predetermined site. Bloodoxygen levels (e.g., pO₂) may be maintained, adjusted, or otherwisecontrolled by controlling the flow rates or by providing controlledamounts of the blood and/or oxygen gas. Thus, a blood-gas control methodis provided.

Liquid-to-Liquid Oxygenation Assemblies

In another embodiment, the intermediate portion of the fluid conduitadapted for oxygenating the blood supplied by the blood pump comprisesan assembly including a mixing region in which an oxygenated fluid,e.g., an oxygen-supersaturated fluid, combines with the blood.Advantageously, the mixing region is defined by a chamber-like assemblyincluding an injection zone in which the oxygenated fluid mixes with theblood at a higher pressure than the target pO₂ for the blood.Oxygenation of the blood occurs as a result of convective mixinginvolving the two contacting fluids and to a lesser extent as a resultof oxygen diffusing directly from the oxygenated liquid to the blood,i.e., dispersion. The mixing advantageously is a convective mixing thatoccurs rapidly and completely.

In one embodiment, the chamber-like assembly comprises a mixing chamberincluding a generally elongated cylindrically-shaped or tubular assemblyhaving upper and lower ends, each end having a cap or similar devicefixedly attached thereto, so as to define an interior space therein.Advantageously, the mixing chamber includes in fluid communication withthe interior space a first inlet port adapted for receiving a supply ofblood to be oxygenated; a second inlet port adapted for receiving asupply of oxygenated fluid to be mixed with the blood; and an exit portadapted for delivery of the oxygenated blood to a particular desiredlocation.

To promote mixing of the blood and oxygenated fluid within the chamberinterior space, the blood to be oxygenated advantageously enters themixing chamber from a location and in a direction so that a vortical orcyclonic flow of blood is created within the chamber. Advantageously,the blood enters the chamber along a path substantially tangential tothe chamber wall. Advantageously, the oxygenated liquid enters thechamber proximate the blood inlet, and the oxygenated blood exits thechamber through a port in the bottom of the chamber. Moreadvantageously, the oxygenated liquid enters the chamber in a generallyupward direction normal to the initial direction of travel of the bloodentering the chamber.

The mixing chamber advantageously is pressurizeable, with the lowerportion of the chamber accumulating a supply of blood and the upperportion including a gas head. The gas head advantageously helps dampenthe pulsatility of the blood entering the chamber.

The oxygenated fluid advantageously comprises an oxygen-supersaturatedfluid in which the dissolved oxygen content would occupy a volume ofbetween about 0.5 and about 3 times the volume of the solvent normalizedto standard temperature and pressure. Examples of solvents which may beused include saline, lactated Ringer's, and other aqueous physiologicsolutions. The oxygenated fluid advantageously is delivered to themixing chamber via one or more capillaries having an internal diameterin the range of about 15 to about 700 μm (advantageously, about 100 μm),the capillaries forming a continuous fluid flow pathway between themixing chamber and a supply or an assembly for providing a supply of theoxygenated fluid.

The oxygenated fluid typically will be supplied to the mixing chamber inaccordance with parameters specified and selected by the caregiver forthe desired clinical indication. The flow of oxygenated fluid isgenerally steady and continuous, although variable or intermittent flowsmay be used. Flow rates may range from about 0.1 cc/min to about 40cc/mm, although particularly advantageous flow rates may be betweenabout 2 cc/min and 12 cc/min. Oxygen concentrations normalized tostandard temperature and pressure may range from about 0.1 ml O₂ per mlphysiologic solution to about 3 ml O₂ per ml physiologic solution,although particularly advantageous concentrations may be about 1 ml O₂per ml physiologic solution.

In another embodiment, a method is provided for the preparation anddelivery of oxygenated blood. The method comprises providing a chamberassembly in which blood and an oxygenated liquid, e.g., anoxygen-supersaturated liquid, mix under pressure to form oxygenatedblood. The method may include the step of controlling or providingcontrolled amounts of blood and oxygenated liquid to the chamberassembly to maintain, adjust or otherwise control blood oxygen levels.Thus, an alternate embodiment blood-gas control method is provided.

Temperature

The oxygenated blood advantageously is provided to the patient at about37° C., i.e., system operation does not significantly affect patientblood temperature. However, in some instances, cooling of the oxygenatedblood may be desired, e.g., to induce local or regional hypothermia(e.g., temperatures below about 35° C.). By way of example only, inneurological applications such cooling may be desired to achieve aneuroprotective effect. Hypothermia also may be regarded as anadvantageous treatment or preservation technique for ischemic organs,organ donations, or reducing metabolic demand during periods of reducedperfusion.

Accordingly, the system provided may include a heat exchanger assemblyoperable to maintain, to increase, or to decrease the temperature of theoxygenated blood as desired in view of the circumstances involved in aparticular application. Advantageously, temperatures for the oxygenatedblood in the range of about 35° C. to about 37° C. generally will bedesired, although blood temperatures outside that range (e.g., perhapsas low as 29° C. or more) may be more advantageous provided that patientcore temperature remains at safe levels in view of the circumstancesinvolved in the particular application. Temperature monitoring mayoccur, e.g., with one or more thermocouples, thermistors or temperaturesensors integrated into the electronic circuitry of a feedbackcontrolled system, so that an operator may input a desired perfusatetemperature with an expected system response time of seconds or minutesdepending upon infusion flow rates and other parameters associated withthe active infusion of cooled oxygenated blood.

Examples of heat exchange assemblies suitable for use with the presentsystem, either alone or integrated with a system component, include anyof the numerous commercially available and clinically accepted heatexchanger systems used in blood delivery systems today, e.g., heatexchangers, heat radiating devices, convective cooling devices andclosed refrigerant devices. Such devices may include, e:g.,conductive/convective heat exchange tubes, made typically of stainlesssteel or high strength polymers, in contact with blood on one side andwith a coolant on the other side.

In another embodiment, in a liquid-to-liquid oxygenation assembly,cooled oxygenated blood is provided by mixing blood with a cooledoxygenated liquid, e.g., an oxygen-supersaturated liquid. Anycommercially available and clinically acceptable heat exchange systemmay be used to cool the oxygenated liquid and/or cool the oxygenatedblood. Because most gases show increased solubility when dissolved intoaqueous liquids at low temperatures (e.g., oxygen solubility in waterincreases at a rate of 1.3% per degree Celsius decrease) such a methodoffers the added benefit of enhanced stability of the oxygenated blood,which in some cases may enable increased oxygen concentrations.

Bubble Detection and Other Assemblies

The system may include one or more gas bubble detectors, at least one ofwhich is capable of detecting the presence of microbubbles, e.g.,bubbles with diameters of about 100 μm to about 1000 μm. In addition,the system may include one or more macrobubble detectors to detectlarger bubbles, such as bubbles with diameters of about 1000 μm or more.Such macrobubble detectors may comprise any suitable commerciallyavailable detector, such as an outside, tube-mounted bubble detectorincluding two transducers measuring attenuation of a sound pulsetraveling from one side of the tube to the other. One such suitabledetector may be purchased from Transonic Inc. of New York.

The microbubble and macrobubble detectors provide the physician orcaregiver with a warning of potential clinically significant bubblegeneration. Such warnings also may be obtained through the use oftransthoracic 2-D echo (e.g., to look for echo brightening of myocardialtissue) and the monitoring of other patient data.

Advantageously, the bubble detection system is able to discriminatebetween various size bubbles. Further, the bubble detection systemadvantageously operates continuously and is operatively coupled to theoverall system so that an overall system shutdown occurs upon thesensing of a macrobubble.

The system also may include various conventional items, such as sensors,flow meters (which also may serve a dual role as a macrobubbledetector), or other clinical parameter monitoring devices; hydrauliccomponents such as accumulators and valves for managing flow dynamics;access ports which permit withdrawal of fluids; filters or other safetydevices to help ensure sterility; or other devices that generally mayassist in controlling the flow of one or more of the fluids in thesystem. Advantageously, any such devices are positioned within thesystem and used so as to avoid causing the formation of clinicallysignificant bubbles within the fluid flow paths, and/or to prevent fluidflow disruptions, e.g., blockages of capillaries or other fluidpathways. Further, the system advantageously comprises a biocompatiblesystem acceptable for clinical use with human patients.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects and advantages of the present invention will becomeapparent upon reading the following detailed description and uponreferring to the accompanying drawings in which:

FIG. 1 is a schematic diagram illustrating an exemplary embodiment of asystem for oxygenating blood in accordance with the present invention.

FIG. 2 is a schematic diagram illustrating an exemplary embodiment of ablood oxygenation assembly including a high pressure membrane oxygenatorin accordance with the present invention.

FIG. 3 is a cross-sectional view of an exemplary embodiment of a highpressure membrane oxygenator in accordance with the present invention.

FIG. 4 is a schematic diagram illustrating an exemplary embodiment of anextracorporeal circuit including a blood oxygenation system having ahigh pressure membrane oxygenator in accordance with the presentinvention.

FIG. 5 is a schematic diagram illustrating an exemplary embodiment of anoxygenation assembly including a liquid-to-liquid oxygenation assemblyin accordance with the present invention.

FIG. 6 is a schematic diagram illustrating an exemplary embodiment of anextracorporeal circuit including a blood oxygenation system having aliquid-to-liquid oxygenation assembly in accordance with the presentinvention.

FIG. 7A is a vertical cross-sectional view of an exemplary embodiment ofa liquid-to-liquid oxygenation assembly in accordance with the presentinvention

FIG. 7B is a top view of the exemplary embodiment of theliquid-to-liquid oxygenation assembly shown in cross-sectional view inFIG. 7A.

FIG. 7C is a bottom view of the exemplary embodiment of theliquid-to-liquid oxygenation assembly shown in cross-sectional view inFIG. 7A.

FIG. 7D is a partial cut away view of the lower portion of theliquid-to-liquid oxygenation assembly shown in cross-sectional view inFIG. 7A.

FIG. 7E is a cross sectional view taken along the line E—E of the lowerportion of the liquid-to-liquid oxygenation assembly shown incross-sectional view in FIG. 7D.

FIG. 8 is a partial cut away view of an exemplary embodiment of acatheter assembly for delivery of oxygenated blood in accordance withthe present invention.

FIG. 8A is a cross-sectional view of the exemplary catheter assemblyshown in FIG. 8 taken along the line A—A.

FIG. 8B is a cross-sectional view of the exemplary catheter assemblyshown in FIG. 8 taken along the line B—B.

FIG. 8C is a cross-sectional view of the exemplary catheter assemblyshown in FIG. 8 taken along the line C—C.

FIG. 8D is a cross-sectional view of the exemplary catheter assemblyshown in FIG. 8 taken along the line D—D.

FIG. 8E is a cross-sectional view of the exemplary catheter assemblyshown in FIG. 8 taken along the line E—E.

FIG. 8F is an end view of the tip of the exemplary catheter assemblyshown in FIG. 8.

FIG. 9 is a schematic diagram illustrating an exemplary embodiment of anoxygenated blood fluid delivery apparatus in accordance with the presentinvention.

FIG. 10 is a schematic diagram illustrating an exemplary embodiment of asystem for supplying an oxygen-supersaturated fluid.

FIG. 11 is a schematic diagram illustrating an alternate exemplaryembodiment of a system for supplying an oxygen-supersaturated fluid.

FIG. 12 is a graph, for an exemplary oxygenated blood fluid deliveryapparatus, of oxygenated blood pressure at the oxygenation assembly as afunction of blood flow rate and effective catheter inner diameter, inaccordance with the present invention.

FIG. 13 is a graph, for an exemplary oxygenated blood fluid deliveryapparatus, of oxygenated blood pressure at the oxygenation assembly as afunction of effective catheter inner diameter and hematocrit, inaccordance with the present invention.

FIG. 14 is a graph, for an exemplary oxygenated blood fluid deliveryapparatus, of predicted oxygenated blood pO₂ as a function of oxygenatedfluid pO₂ and patient systemic pO₂, in accordance with the presentinvention.

FIG. 15 is a graph, for an exemplary oxygenated blood fluid deliveryapparatus, of predicted oxygenated blood pO₂ as a function of oxygenatedfluid pO₂ and blood flow rate, in accordance with the present invention.

FIG. 16 is a graph, for exemplary embodiments of a high pressuremembrane oxygenator, of oxygenator efficiency as a function ofoxygenator length for an exemplary blood flow rate, in accordance withthe present invention.

The present invention may be susceptible to various modifications andalternative forms. Specific embodiments of the present invention areshown by way of example in the drawings and are described herein indetail. It should be understood, however, that the description set forthherein of specific embodiments is not intended to limit the presentinvention to the particular forms disclosed. Rather, all modifications,alternatives, and equivalents falling within the spirit and scope of theinvention as defined by the appended claims are intended to be covered.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

The description below illustrates embodiments of the present invention.For the sake of clarity, not all features of an actual implementation ofthe present invention are described in this specification. It should beappreciated that in connection with developing any actual embodiment ofthe present invention many application-specific decisions must be madeto achieve specific goals, which may vary from one application toanother. Further, it should be appreciated that any such developmenteffort might be complex and time-consuming, but would still be routinefor those of ordinary skill in the art having the benefit of thisdisclosure.

For the sake of clarity and convenience, the various embodiments aredescribed herein in the context of interventional cardiovascularapplications generally involving acute or transient ischemia orpost-ischemic tissues. However, the present invention may also be usefulin other medical applications, such as cancer therapy (e.g., thedelivery of oxygen-enriched fluids directly into poorly vascularizedtumors during radiation or chemotherapy treatments), neurovascularapplications (e.g., the treatment of stroke and cerebral traumapatients), lung support in trauma and lung disease patients, and woundcare management.

Also, although the present invention may be used to raise oxygen levels,for example, in venous and arterial blood, in blood substitutes, e.g.,perfluorocarbons, and in combinations thereof, for the sake of clarityand convenience reference is made herein only to arterial blood.

Further, the present invention also may be used in connection with drugfluid infusion therapies to prevent ischemia and/or to otherwise enhancethe effectiveness of the therapies. Examples of drug fluids used incardiovascular and neurological procedures which may be infused (eitherbefore, after or along with the oxygenated blood) in accordance with thepresent invention include, without limitation, vasodilators (e.g.,nitroglycerin and nitroprusside), platelet-actives (e.g., ReoPro andOrbofiban), thrombolytics (e.g., t-PA, streptokinase, and urokinase),antiarrhythmics (e.g., lidocaine, procainamide), beta blockers (e.g.,esmolol, inderal), calcium channel blockers (e.g., diltiazem,verapamil), magnesium, inotropic agents (e.g., epinephrine, dopamine),perofluorocarbons (e.g., fluosol), crystalloids (e.g., normal saline,lactated ringers), colloids (albumin, hespan), blood products (packedred blood cells, platelets, whole blood), Na+/H+ exchange inhibitors,free radical scavengers, diuretics (e.g., mannitol), antiseizure drugs(e.g., phenobarbital, valium), and neuroprotectants (e.g., lubeluzole).The drug fluids may be infused either alone or in combination dependingupon the circumstances involved in a particular application, and furthermay be infused with agents other than those specifically listed, such aswith adenosine (Adenocard, Adenoscan, Fujisawa), to reduce infarct sizeor to effect a desired physiologic response.

Turning now to the drawings, a system is provided in which blood isoxygenated, e.g., for delivery to a particular predetermined area withina patient's body for the treatment of conditions such as tissue ischemiaand post-ischemic tissues. As shown schematically in FIG. 1, oneembodiment of such a system includes a blood pump assembly 20 adaptedfor receiving a supply of blood from a blood supply assembly 10. Theblood supply assembly 10 may comprise a supply of blood provided forinfusion to a patient or to another particular desired location. By wayof example, and without limitation, the supply of blood may be receivedfrom a bag or other blood container; from a blood transferring device,such as a heart bypass system, blood oxygenator, blood filtrationassembly, artificial heart and the like; from another individual; orfrom the patient.

The pump assembly 20 provides the blood to a blood oxygenation assembly30. The oxygenation assembly 30 comprises an apparatus for raising thepO₂ of the blood, advantageously to hyperoxemic or hyperbaric levels. Inone embodiment, the oxygenation assembly comprises a high pressuremembrane oxygenator. In another embodiment, the oxygenation assemblycomprises a liquid-to-liquid oxygenator.

The oxygenation assembly 30 oxygenates blood received from the pumpassembly 20. The oxygenated blood is then provided to a deliveryassembly 40 for delivery to a desired location. Advantageously, bloodoxygenation occurs at least in part at a pressure greater thanatmospheric pressure, and the oxygenated blood is delivered with aconcomitant pressure drop, so that the formation of clinicallysignificant bubbles is avoided, i.e., blood oxygenation and deliveryoccurs bubble-free.

What constitutes bubble-free delivery will vary depending upon thecircumstances involved in a particular application. Advantageously,bubble-free delivery will occur with a complete absence of bubbles.However, in some cases of “bubble-free” delivery, one or more (perhapsmaybe even thousands of) non-clinically-significant bubbles may bedelivered, particularly where the gas bubbles comprise oxygen gasbubbles, which are thought to be more readily accepted by the body thanbubbles of other gases. Moreover, a clinically acceptable level ofbubbles in one application (e.g., a coronary procedure) might not proveto be clinically acceptable in another application (e.g., a neurologicalprocedure).

Little hard data are available. However, for interventional cardiologyapplications, for example, one factor addressing the question of whatconstitutes a clinically significant bubble may be the total volume ofgas, per kilogram body weight, delivered into the coronary circulation.In cases where the gas is air (as opposed to cases involving oxygen gasbubbles), experienced angiographers have witnessed a single bubble ormultiple bubbles up to approximately 3 mm (3000 μm) in diameter,embolize into a coronary artery of a patient during an angiographicprocedure without a resulting clinical problem. The volume of air in a 3mm diameter bubble is approximately 14 microliters. Thus, this volume ofair, embolized as a single bubble into a human coronary artery isbenign. Moreover, Khan et al. (1995) Coronary Air Embolism: Incidence,Severity, and Suggested Approaches to Treatment, Catheterization andCardiovascular Diagnosis 36:313-18, retrospectively studied 3715coronary angiograms to assess the incidence and severity of coronary airembolism, and related clinical severity to bubble volume as follows:minimal (several bubbles that disappear immediately without symptoms);mild (1 ml air with mild, transient symptoms); moderate (2-3 ml airusually associated with severe symptoms); and massive (>3-5 ml airassociated with serious, life threatening complications). The mildclinical effect observed with 1 ml of air in the study is aboutequivalent to experiencing a single bubble with a 12 mm diameter, sincethe volume of this bubble is 1 ml. Thus, it appears that a 3 mm diameterair bubble is clinically insignificant—it is a minimal volume of air perunit body weight.

Accordingly, for a coronary application in which the primary bubbles ofinterest are oxygen bubbles, it is believed that a total delivered gasvolume of less than between about 1-2 ml represents clinicalinsignificance. However, because oxygen is metabolically consumed,oxygen bubble infusion is not thought to be as traumatic as the infusionof inert gases (e.g., nitrogen).

Turning now to FIG. 2, an exemplary oxygenation assembly is depictedschematically including a high pressure membrane oxygenator assembly 50.The membrane oxygenator assembly 50 includes a membrane 52 in effectdividing the assembly 50 into two separate fluid compartments: a gasside compartment 54 and a blood side compartment 56. Oxygen gas from anoxygen gas supply assembly 58 is provided to the interior of thecompartment 54 at a pressure P1. Advantageously, the assembly 58 is aregulated oxygen bottle and the pressure P1 is a pressure greater thanatmospheric and less than about 30 p.s.i.a. Most advantageously, thepressure P1 is about 2 atmospheres. Blood to be oxygenated is providedby a blood supply assembly 60 to the interior of compartment 56 at apressure P2. Advantageously, the pressure P2 is greater than about P1,and bulk gas flow across the membrane 52 is avoided.

As the oxygen gas is provided to the compartment 54 and the bloodprovided by the blood supply assembly 60 flows through the compartment56, oxygen diffuses across the membrane 52 to oxygenate the blood.Oxygenated blood exits the compartment 56 via a line 62, e.g., fordelivery via a catheter to a patient's body.

In an alternate embodiment the membrane oxygenator assembly is adaptedwith a bulk gas exit vent 64, so that gas may flow through thecompartment 54 when the vent 64 is open. Advantageously, the vent 64includes an adjustable valve or other means operable to control the rateof gas flow through compartment 54 for a given pressure P1. The fluidstream exiting compartment 54 may be vented to the atmosphere or tosuitable means for processing and disposing of the exiting fluid.Depending upon the circumstances involved in a particular application,gases may diffuse across the membrane 52 from the blood flowing throughthe compartment 56 to join the stream exiting compartment 54.

The form which the membrane oxygenator assembly 50 may take, and itsexact size and shape, may vary depending upon the circumstances involvedin a particular application. By way of example only, and withoutlimitation as to the scope of the present invention, the membraneoxygenator assembly 50 may comprise an external flow fiber bundleoxygenator in which the compartment 54 comprises a plurality of hollowfibers through which gas may flow; the compartment 56 comprises ahousing or vessel surrounding the hollow fibers and within which bloodprovided to the interior of the housing or vessel may contact the outersurface of the hollow fibers; and the membrane 52 comprises the totalactive surface area of the hollow fibers across which oxygen diffuseswhen blood is provided to the interior of the housing or vessel andoxygen gas is provided to the interior of the hollow fibers.

In an alternate embodiment (see FIG. 3), the high pressure membraneoxygenator comprises an internal flow hollow-fiber type blood oxygenatorassembly. Advantageously, the assembly includes a generallycylindrically shaped housing assembly loosely packed with a plurality ofhollow fibers 70. The housing advantageously comprises a generallytubular main body portion 72 having first and second ends; and end caps74, 76 fixedly attached (e.g., with UV adhesive) to the first and secondends, respectively. The ends of the hollow fibers 70 advantageously aresecured within the housing assembly by a potting material, e.g., apolyurethane resin. Advantageously, the potting material forms fluidbarriers 78, 80 proximate the first and second ends, respectively. Thehollow fibers 70 extend through the barriers 78, 80, so that the housingassembly comprises four fluid flow regions within the housing assembly:a blood inlet manifold 82, comprising the fluid space defined by thebarrier 78 and cap 74; a blood outlet manifold 84, comprising the fluidspace defined by the barrier 80 and the cap 76; an oxygen chamber 86,comprising the fluid space defined by the barriers 78, 80, the housingbody portion 72, and the external surfaces of the hollow fibers 70; andthe interior of hollow fibers 70, which region comprises a plurality ofcontinuous fluid pathways between the blood inlet and outlet manifolds82, 84.

Advantageously, the end cap 74 includes a blood inlet port 88, and thecap 74 is adapted with a luer connector 92 for releasably coupling theoxygenator assembly to an apparatus for providing a supply of blood tobe oxygenated. The end cap 76 includes a blood exit port 90, and the cap76 is adapted with a luer connector 94 for releasably coupling theoxygenator assembly to an oxygenated blood delivery apparatus, e.g., atube and catheter or infusion guidewire. The housing body portion 72includes gas inlet and outlet ports 96, 98, respectively. The gas inletport 96 advantageously is adapted with a luer connector 100 forreleasably coupling the oxygenator assembly to an oxygen gas supplyassembly. The gas outlet port 98 advantageously is adapted with a luerconnector 102 for releasably coupling the oxygenator assembly to anapparatus for venting the stream of gas exiting the oxygenator assemblyto the atmosphere or to a filter assembly prior to disposal.

Thus, a method is provided in which oxygen is supplied to the oxygenchamber 86 at a pressure above atmospheric. Blood enters the blood inletmanifold 82 via port 88 and travels through the hollow fibers 70 whereoxygenation of the blood occurs by virtue of oxygen diffusion across thefibers 70. Bulk gas transfer is avoided by maintaining the bloodpressure greater than the gas pressure. The oxygenated blood then exitsthe oxygenator assembly via blood outlet manifold 84 and port 90 fordelivery to a given location.

The hollow fibers 70 advantageously comprise a 160 cm length of mattedfibers (each fiber advantageously about 8-10 cm in length) looselyrolled into a cylindrical shape, so that about a 0.05 inch space remainsbetween the outer diameter of the fiber roll and the inner diameter ofthe oxygenator housing. The ends of the fibers proximate the entranceand exit manifolds advantageously are open and clean. A particularlyadvantageous matted fiber commercially available for use is the AkzoOxyphan™ fiber mat, a polyproplyene hollow fiber mat including 16.8fibers/cm, each fiber having a wall thickness of about 50 μm and about a280 μm inner diameter, available from Akzo Nobel, Germany.

For a given input blood pO₂ and a specified oxygen pressure on the gasside of the membrane, as well as a specified blood flow rate and fiberhousing diameter, a membrane oxygenator length can be determined toensure equilibrium oxygen saturation. Of course, many variations arepossible. By way of example only, and without limitation, a unit havinga diameter of about 4 cm and length of about 10 cm, with a void volumeof about 0.4 for fibers of about 380 μm O.D. and about 280 μm I.D., issufficient to achieve equilibrium saturation for a blood flow rate ofabout 200 ml/min. Such a device would have a total blood priming volumeof about 41 ml. Of course lower blood flow rates, smaller diameterfibers, tighter fiber packing, and overdriving the oxygen pressure willreduce the size requirement of the device, which is independent ofdesired blood pO₂. In any event, the extensive characterization of masstransfer coefficients that is typically required for external blood flowmembrane oxygenators is unnecessary, and smaller priming volumes may beachieved.

In one embodiment, oxygen transfer to the blood may be approximatedusing a model based on the convective-diffusion equation which considersblood flow through a circular tube as a variant of theGraetz-Nusselt-Leveque mass transfer problem for diffusion of solutethrough the walls of a tube in which the solvent experiences laminarHagen-Poiseuille flow. Under this model, for oxygen supplied through thetube walls at a partial pressure equal to the pressure of oxygen gassupplied to the oxygenator, as shown by way of example in FIG. 16,oxygenator size may be determined through application into the model ofseveral variables (e.g., blood flow rate, oxygen solubility, the numberand/or size of the fibers, oxygen diffusivity in the blood, etc.). For adesired maximum blood flow rate Q_(max), oxygenator size advantageouslyis minimized so that a desired efficiency β may be achieved, where β isthe ratio of the outlet blood pO_(2(out)) and the oxygen gas pressure.As shown in FIG. 16, for a blood flow rate of 75 ml/min with anoxygenator including 4100 fibers of 280 μm internal diameter, anoxygenator length of about 6 cm or more results in an efficiency β=1.

Other models for determining oxygen transfer also may be used, e.g.,models based on empirical evidence of mass transfer coefficients, ormass transfer models tailored for specific applications involving othermass transfer boundary conditions, flow geometries, fluids, operatingparameters, etc. Advantageously, the oxygen transfer model may be usedto characterize an oxygenator to promote its selection by a caregiverfor a particular application. In one embodiment, a method is providedincluding the steps of using an oxygen transfer model to characterize anoxygenator assembly to promote selection of the device for anapplication in which oxygenated blood is to be provided to the patientat a desired flow rate and pO₂. More advantageously, the oxygenatedblood is provided at a pO₂ level greater than about 760 mm Hg.

Because the device advantageously may be designed for equilibrium masstransfer, equilibrium heat transfer may occur also. Thus, a systemrequirement may include means for controlling the temperature of theblood exiting the assembly. By way of example, a simple heating devicemight include, e.g., an electric blanket wrapped around the oxygenatorunit, with feedback control, for maintaining the temperature of theblood at about 37 ° C.

Turning to FIG. 4, an extracorporeal circuit for oxygenating bloodincluding a high pressure membrane oxygenator 110 is shown. The systemrequirements may include a blood pump assembly 112 and an oxygen gassupply assembly 114 operatively coupled to the high pressure membraneoxygenator 110. Other components may include blood temperature controldevices, bubble detection apparatus, pressure/temperature sensors, pO₂sensors, etc. (not shown in FIG. 4). Advantageously, the various systemcomponents are operatively coupled to a processing and control assembly116 including electronic circuitry to enable the sending and receivingof signal inputs and/or control commands amongst one or more of thevarious system components. A display assembly 118 coupled to theprocessing and control assembly 116 may serve as a separate userinterface for the input of data and/or process control commands and/orfor the display of system status and/or processing outputs.

The flow characteristics of the oxygenated blood exiting the membraneoxygenator assembly 110 will depend upon the circumstances surroundingthe particular application involved. Typically, for example, the supplyof oxygenated blood provided to a catheter for infusion to a patient'sbody will be a controlled flow defined by the flow parameters selectedby the caregiver. In an application involving the sub-selective deliveryof oxygenated blood for the treatment of ischemic tissues and/or theprevention of ischemia, flow rates of about 75-100 ml/min may beadvantageous. Again, factors influencing the determination of blood flowcharacteristics may include one or more of the many clinical parametersor variables of the oxygenated blood to be supplied to the catheter orto be delivered to the patient, e.g., the size of the patient, thepercentage of overall circulation to be provided, the size of the bloodvessel to be accessed, hemolysis, hemodilution, pO₂, pulsatility, massflow rate, volume flow rate, temperature, hemoglobin concentration andpH.

Turning to FIG. 5, shown schematically is an alternate embodiment of anoxygenation assembly including a liquid-to-liquid oxygenation assembly200. The assembly 200 advantageously combines a supply ofoxygen-supersaturated fluid received from a supply assembly 210 with asupply of blood received from a supply assembly 220 to form oxygenatedblood for delivery to a given location.

In one embodiment, the oxygen-supersaturated fluid advantageouslyincludes a dissolved oxygen volume normalized to standard temperatureand pressure of between about 0.5 and about 3 times the volume of thesolvent. The fluid may be supplied to the system at a pressure ofbetween about 100 p.s.i. and about 5000 p.s.i., more advantageouslybetween about 100 p.s.i. and 600 p.s.i., although the exact pressure mayvary depending upon the circumstances involved in a particularapplication. Further, the oxygen-supersaturated fluid supplied may besterile and have a delivery path which does not include gas or surfacesites at which potentially clinically significant bubbles may nucleateand/or grow.

As described herein, one preferred fluid for use in accordance with thepresent invention is an oxygen-supersaturated fluid. However, othergas-supersaturated fluids may be used depending upon the circumstancesinvolved in a particular desired application, such as, for example,supersaturated fluids in which one or more gases such as helium, nitrousoxide, carbon dioxide and air are dissolved.

Exemplary apparatus and methods for the preparation and delivery ofoxygen-supersaturated fluids are disclosed in U.S. Pat. No. 5,407,426 toSpears entitled “Method and Apparatus for Delivering Oxygen into Blood”;U.S. Pat. No. 5,569,180 to Spears entitled “Method for Delivering aGas-Supersaturated Fluid to a Gas-Depleted Site and Use Thereof”; U.S.Pat. No. 5,599,296 to Spears entitled “Apparatus and Method of Deliveryof Gas-Supersaturated Liquids”; and U.S. Pat. No. 5,893,838 to Daoud etal. entitled “System and Method for High Pressure Delivery ofGas-Supersaturated Fluids”; each of which is incorporated herein byreference. Furthermore, disclosure relating to exemplary apparatus andmethods for the preparation and/or use of gas-supersaturated fluids,including, e.g., oxygen-supersaturated fluids, in various applications,may be found in the following patents and patent applications, each ofwhich is incorporated herein by reference: copending U.S. patentapplication Ser. No. 08/581,019, filed Jan. 3, 1996, which is acontinuation in part of U.S. patent application Ser. No. 273,652, filedJul. 12, 1994, now U.S. Pat. No. 5,569,180, which is a continuation inpart of U.S. patent application Ser. No. 152,589, filed Nov. 15, 1993,now U.S. Pat. No. 5,407,426, which is a continuation in part of U.S.patent application Ser. No. 818,045, filed Jan. 8, 1992, now U.S. Pat.No. 5,261,875, which is a continuation of U.S. patent application Ser.No. 655,078, filed Feb. 14, 1991, now U.S. Pat. No. 5,086,620.

In an alternate embodiment (see FIG. 10), the oxygen-supersaturatedfluid supply assembly comprises an apparatus including a chamber 300coupled to a regulated source of oxygen gas 310 that maintains a desiredpressure in the chamber 300. Advantageously, the chamber volume is about100 ml, and the pressure in the chamber 300 is about 600 p.s.i. Aphysiologic fluid (e.g., saline) enters the chamber 300 through a nozzle320 . The nozzle 320 advantageously forms fluid droplets into whichoxygen diffuses as the droplets travel within the chamber 300. Moreadvantageously, the nozzle 320 comprises an atomizer nozzle adapted toform a droplet cone 330 definable by an included angle α, whichadvantageously is about 20 to about 40 degrees at operating chamberpressures (e.g., about 600 p.s.i.) for a pressure drop across the nozzle320 of greater than approximately 15 p.s.i. The nozzle 320 is asimplex-type, swirled pressurized atomizer nozzle including a fluidorifice of about 100 μm diameter. Advantageously, the nozzle 320 formsfine fluid droplets of less than about 100 μm diameter, and moreadvantageously of about 25 μm. The fluid advantageously is provided tothe chamber 300 by a pump 340 operatively coupled to a fluid supplyassembly 350. The fluid advantageously is provided at a controlled ratebased on the desired oxygen-supersaturated fluid outlet flow rate. Atthe bottom of the chamber 300 , fluid collects to form a pool 360 whichadvantageously includes fluid having a dissolved gas volume normalizedto standard temperature and pressure of between about 0.5 and about 3times the volume of the solvent. The fluid is removed from the chamber300 (e.g., via a pump 370, which advantageously permits control of theflow rate, or by virtue of the pressure in the chamber 300 ) fordelivery to a given location (e.g., to a blood oxygenation assembly).

More advantageously, as shown in FIG. 11, oxygen-supersaturated fluid isproduced by atomizing a physiologic liquid such as saline provided froma supply assembly 400 into a chamber 410 pressurized to about 600 p.s.iby oxygen. The oxygen advantageously is provided to the chamber 410 froman oxygen supply assembly 412, e.g., a medical grade E-bottle.

Saline advantageously is provided to the chamber 410 (e.g., from asaline bag or other container) via nozzle 411 by a piston-like assemblycomprising an syringe pump 416 capable of delivering 600+ p.s.i. salineeither continuously or intermittently depending upon the circumstancesinvolved in a particular application. The syringe pump 416advantageously includes a piston 418 operatively coupled to a motorassembly 420. A check valve 422 prevents unwanted loss of fluid from theline 413 during filling of the syringe pump 416. A check valve 424prevents unwanted flow of saline to the fluid supply assembly 400 asfluid exits the syringe pump 416. Advantageously, the syringe pump 416includes a fluid reservoir having a volume of about 10 to about 100 ml,although different size syringe pumps may be used depending upon thecircumstances involved in a particular application. In addition, thechamber inlet advantageously is filtered to protect from any debris thatmight be present in the pumping system.

Three needle valves 426, 428, 430 advantageously are used to control theflow of fluid to and from the chamber 410. Table II describes the modesof operation for the needles. During normal operation, the pumpingsystem is off and only the delivery valve (needle 430) is open to allowfluid delivery from the chamber 410 via fluid exit lumen 401 and theassembly outlet 402, e.g., to a blood oxygenation assembly. When thechamber needs to be filled (e.g., in response to a sensor signalindicating that the fluid level in the chamber has dropped to apredetermined level), a two-part filling sequence advantageously begins.In part one of the filling sequence, the pumping system is on anddilution flow is on, i.e., dilution valve (needle 426) is open to allowfluid delivery from the line 413 to the chamber 410 via line 403. Inpart two, needle 426 is closed, and flow is directed from line 413through the atomizer nozzle 411 via line 405. The delivery valve (needle430) remains open during both parts of the filling sequence. By varyingthe time of each part of the filling sequence, the concentration of thefluid in the chamber can be varied. For example, to achieve a 300 p.s.i.concentration in a chamber pressurized to 600 p.s.i., for a 40 secondtotal fill time each part of the two-part filling sequence would lastabout 20 seconds. Check valve 434 prevents backflow from the chamberthrough the atomizer nozzle to the pumping system as the pumping systemreservoir is being filled. Advantageously, check valve 434 includes aball which seats under pressure against a portion of the valve body toprevent unwanted backward fluid flow. Further, to bypass the chamber,i.e., so that fluid neither enters nor exits the chamber, a flushsequence is initiated. During flush, the delivery valve (needle 430) andthe dilution valve (needle 426) are closed, the flush valve (needle 428)is open, and the pumping system is on, so that unoxygenated salinepasses through the system.

TABLE II Pump Valve State State Needle 426 Needle 428 Needle 430 NormalOperation Off Closed Closed Open Filling Sequence Part 1 On Open ClosedOpen Part 2 On Closed Closed Open Flush sequence On Closed Open Closed

Advantageously, each of the needles 426, 428, 430 is opened and closedeither independently or in conjunction with the opening or closing ofone or more other needles, to achieve a desired flow ofoxygen-supersaturated fluid from the assembly. The actuator assembly 432may comprise switching means, e.g., solenoids, operatively coupled toeach valve to move the valves between open and closed positions.

The chamber 410 advantageously comprises a disposable housing 415 andcap 417 joined (e.g., by threaded engagement) or fixedly attached (e.g.,by UV adhesive) so as to define the interior space into which saline andoxygen are introduced. The chamber 410 further may include a bacterialfilter assembly 414 for removing unwanted particulates from the gasentering the chamber 410. The housing 415 and cap 417 may be formed ofpolycarbonate or of another suitable biocompatible material.

For safety, the chamber 410 may be disposed at least in part within aprotective housing assembly 438, comprising, e.g., a stainless steelholder. In one embodiment, a block 419 may be positioned within theholder 438 above the chamber 410. Advantageously, the block 419 isadapted with a recess or generally concave-shaped lower surface portion,so that a gas plenum 421 is defined by the lower surface of the block419 and the upper end or surface of the chamber 410. Advantageously, theboundary between the block 419 and chamber 410 is sealed (e.g., with ano-ring, gasket or other sealing means). A ring 423 in threadedengagement with the holder 438 may help retain the block 419 sealed andin place against chamber 410 when oxygen gas from the supply assembly412 is introduced into the plenum 421 through a gas inlet port in theblock 419. From the plenum 421 gas may enter the chamber 410 through thefilter 414 disposed along a port through the cap 417. Advantageously,gas pressure within the plenum 421 and the chamber 410 are about equal.

Advantageously, the chamber 410 and other system components include oneor more sensors, e.g., fluid level sensors, pressure tranducers, etc.,(not shown in FIG. 11) to enable the monitoring of system status duringoperation. Advantageously, the sensors and various system components arecoupled to a processing and control assembly 436 including electroniccircuitry to enable the sending and receiving of signal inputs and/orcontrol commands amongst one or more of the various system components. Adisplay assembly 440 coupled to the processing and control assembly 436may serve as a separate user interface for the input of data and/orprocess control commands and/or for the display of system status and/orprocessing outputs.

For the sake of clarity and convenience, oxygen-supersaturated fluidsupply assemblies such as the ones shown in FIGS. 10 and 11 have beendescribed including liquid atomizing assemblies. However, other meansfor contacting the liquid and gas may be used. For example, in somecases it may be desirable to provide the liquid within the pressurizedchamber as a thin film in contact with oxygen gas. The liquid film maybe created, for example, by plates, sieves, screens or other mechanicalmeans either disposed within or forming part of the chamber. Moreover,fluid supply assemblies other than the pump and syringe pumpembodiments, valving arrangements, and/or liquid flow paths shown may beused in combination with the various other components described herein.

Turning now to FIG. 6, an extracorporeal blood oxygenation circuit isshown including a pump assembly 500 operable to deliver blood withdrawnfrom a patient to an exemplary liquid-to-liquid oxygenation assembly600. The assembly 600, portions of which are shown in greater detail inFIGS. 7A-E, advantageously includes an injector housing 610, a sidewallassembly 620, and a cap 630 joined so as to define an interior space 612within which blood provided by the supply tube 640 mixes withoxygen-supersaturated fluid provided by the capillary assembly 650 toform oxygenated blood. The oxygenated blood exits the interior space 612via outlet 614 for delivery via return tube 660 to a fluid deliveryapparatus 510. The injector housing 610, sidewall assembly 620, cap 630,and other assembly components advantageously are disposable and are madeof biocompatible materials, e.g., polycarbonate, polyethelyene and thelike. The tubing advantageously comprises medical grade PVC tubing.

The blood supply tube 640, which may include a pressure monitoring port642, advantageously comprises a continuous blood flow path between afirst tube end operatively coupled to the outlet of the blood pumpassembly 500 and a second tube end fixedly attached to the injectorhousing 610 and in fluid communication with the interior space 612,e.g., via a fluid passageway 644 extending through at least a portion ofthe housing 610 and including a fluid port 646. Advantageously, bloodexits through port 646 so as to create a vortical or cyclonic flowwithin the interior space 612, e.g., along a path substantiallytangential to the chamber wall.

The capillary assembly 650 advantageously includes a single fused silicacapillary having a 100 μm inner diameter and a 350 μm outer diameter,which comprises a continuous fluid pathway between a first end of theassembly 650 operatively coupled to the outlet of anoxygen-supersaturated fluid supply assembly 550 and a second end of theassembly 650 disposed to allow fluid exiting the capillary to enter theinterior space 612 of the liquid-to-liquid oxygenator. Advantageously,the capillary assembly 650 includes between its first and second ends aluer fitting 652 for securing the capillary in place upon beingpositioned within a lumen 654 passing through at least a portion of theinjector housing 610 to the interior space 612. The capillary assemblyadvantageously may further include a support assembly (e.g., a rigidtube within which at least a portion of the capillary is disposed)proximate the second end of the assembly 650 to help maintain thecapillary fluid outlet port in place within the interior space 612,and/or a strain relief assembly (e.g., a flexible tube within which atleast a portion of the capillary is disposed) to help prevent excessivebending or kinking of the capillary.

Alternately, the capillary assembly 650 may comprise a plurality ofcapillaries having inner diameters in the range of about 20 μm to about1000 μm, with an inner diameter of about 100 μm to about 125 μm beingparticularly advantageous. The capillaries advantageously are pottedtogether or otherwise joined at their outer surfaces to form a singlecapillary bundle. The capillaries also may be formed of glass, PEEK(poly ether ether ketone) or other biocompatible material. Treating thecapillaries with a water-wettable coating or liquid rinse prior to usemay prove advantageous to help ensure that the capillary innersurface(s) do not promote clinically significant bubble formation.

Advantageously, the interior space 612 is pressurizable, so that duringoperation a supply of blood accumulates in the bottom and a gas headremains in the top of the liquid-to-liquid oxygenation assembly. The cap630 may be adapted with a port 632 to allowing monitoring of thepressure within the interior space 612. The assembly also may includeone or more fluid sample ports, e.g., port 634 on return tube 660.

The flow characteristics of the oxygenated blood exiting theliquid-to-liquid oxygenation assembly 600 will depend upon thecircumstances surrounding the particular application involved.Typically, for example, the supply of oxygenated blood provided to acatheter for infusion to a patient's body will be a controlled flowdefined by the flow parameters selected by the caregiver. In anapplication involving the sub-selective delivery of oxygenated blood forthe treatment of ischemic myocardial tissues and/or the prevention ofmyocardial ischemia, flow rates of about 75-100 ml/min may beadvantageous. Again, factors influencing the determination of blood flowcharacteristics may include one or more of the many clinical parametersor variables of the oxygenated blood to be supplied to the catheter orto be delivered to the patient, e.g., the size of the patient, thepercentage of overall circulation to be provided, hemolysis,hemodilution, pO₂, pulsatility, mass flow rate, volume flow rate,temperature, target blood vessel, hemoglobin concentration and pH.

It is possible to approximate the pO₂ of the oxygenated blood exitingthe liquid-to-liquid oxygenation assembly 600 for a particularapplication. Advantageously, the processing and control assemblyincludes a computer, electronic circuitry, and/or processing softwareembedded within electronic circuitry (e.g., programmed electronic chips)that continuously executes a pO₂ approximation model during systemoperation that accounts and corrects as necessary for possible pO₂variations resulting from variables such as temperature, pH, Base excess(BE), pCO₂, P₅₀, hemoglobin-oxygen saturation levels, etc. Theprocessing and control assembly advantageously displays model results(e.g., predicted pO₂) for the caregiver on the display assembly alongwith one or more of the input, sensed, calculated or otherwise obtainedvalues of the variables related to the model.

For example, one pO₂ approximation model advantageously may be based onthe Severinghaus equation. See Severinghaus, J. W., Simple, AccurateEquations for Human Blood O₂ Dissociation Computations, Journal ofApplied Physiology 46(3):599-602. Advantageously, the oxygenated fluidpO₂ and oxygen concentration values are adjusted to correct for anydifference between the temperature of the oxygenated fluid entering theliquid-to-liquid oxygenation assembly and the temperature of theoxygenated blood to be infused. The hemoglobin-oxygen saturation iscalculated to estimate the quantity, if any, of oxygen from theoxygenated fluid that will bind to hemoglobin before effecting anincrease in plasma oxygen levels. The difference between the initialoxygen content of the patient's blood and the calculated oxygen contentthat would achieve 100% hemoglobin saturation represents the amount ofoxygen that will be bound by the hemoglobin before plasma pO₂ elevation.By calculating the concentration of the oxygenated fluid delivered intothe flowing blood, and then adjusting that amount downward by an amountequal to the amount of oxygen that will be bound by the hemoglobinbefore plasma pO₂ elevation, the predicted pO₂ can be obtained bycombining the adjusted oxygenated fluid concentration with the initialpatient pO₂.

Exemplary predicted pO₂ values obtained using an approximation modelbased on the Severinghaus equation are set forth in FIGS. 14 and 15.FIG. 14 shows predicted pO₂ as a function of oxygenated fluid pO₂ andpatient systemic pO₂. FIG. 15 shows predicted pO₂ as a function ofoxygenated fluid pO₂ and blood flow rate. Depending upon thecircumstances involved in a particular application, other pO₂approximation models advantageously may be used. Such otherapproximation models may be based, for example, on other equationsand/or methods for determining pO₂, such as those described in Sharan,M., Singh, M. P., Aminataei, A. (1989) A Mathematical Model for theComputation of the Oxygen Dissociation Curve in Human Blood, Biosystems22(3):249-60; and Siggard-Anderson, O., Wimberley, P. D., Gothgen, I.,Siggard-Anderson, M. (1984) A Mathematical Model of theHemoglobin-Oxygen Dissociation Curve of Human Blood and of OxygenPartial Pressure as a Function of Temperature, Clin. Chem.30(10):1646-51.

The delivery apparatus 510 may comprise any clinically acceptable fluiddelivery device such as a catheter (e.g., rapid exchange, over-the-wire,etc.), infusion guidewire, sheath and the like. By way of example only,as shown in FIGS. 8 and 8A-F, one such delivery device comprises acatheter 700 including a proximal end 710 adapted for coupling to theoutlet of an oxygenation assembly (see, e.g., the assemblies shown inFIGS. 4 and 6) and a distal end 720 removably insertable within apatient's body. Advantageously, the catheter 700 includes a relativelystiff proximal portion 730, to provide pushability and torqueability, arelatively flexible distal portion 740, that provides a balance ofstiffness and flexibility to track the vasculature, and a transitionportion 750 of intermediate relative stiffness and flexibility. Thecatheter 700 comprises a generally tubular member having a central lumen760 forming a continuous fluid pathway between the ends 710, 720. Thedistal end 720 of the tubular member may be either open or closed. Thedistal portion 740 of the catheter 700 advantageously includes a secondlumen 780 through at least a portion of its length. The second lumen 780advantageously comprises a guidewire lumen of about 0.017 inch innerdiameter and of sufficient length to promote tracking of the catheterover a 0.014 inch guidewire inserted through the lumen 780, and to allowrapid exchange of the catheter without the use of extension wires. Alumen 780 length of approximately 4 cm, a distal portion 740 length ofabout 5 cm, and an overall catheter length of about 140 cm may beadvantageous, particularly for applications involving the sub-selectivedelivery of oxygenated blood.

Fluid advantageously may exit the central lumen 760 through an end holelocated at the distal tip of the catheter 700 and/or through one or moresideholes 790 disposed along the distal portion 740. Advantageously, thesideholes 790 are located along the portion of the catheter extendingback about 0.5 inches from the distal tip, with sequential sideholesadvantageously spaced so that the sidehole throughway axes are generallyperpendicular to the central axis of the catheter and about parallel toskewed axes circumferentially offset from each other by about 90 degrees(compare, e.g., FIGS. 8D and 8E). The fluid lumen may be of any shape,e.g., D-shaped, kidney-shaped, round, oval, square, etc.

The catheter 700 may include one or more radiopaque marker bands 800 toaid the caregiver in placement of the device. The catheter distal end720 also may include an atraumatic tip, advantageously of 80 shore Ahardness, to promote ease of placement without promoting clinicallysignificant damage to vascular tissues. The proximal shaftadvantageously has a higher shore hardness than the distal shaft toprovide pushability. By way of example, the proximal portion 730 of thecatheter may include a 5 Fr outer diameter, a 3.6 Fr inner diameter andbe made of a 70 shore D material; and the distal portion 740 may includea 3.8 Fr outer diameter, a 2.3 Fr inner diameter fluid lumen 760 and bemade of a 55 shore D material. Materials used to make the catheter 700may include polyethylene or any other suitable biocompatible material(e.g., polyurethane, polyamide, polyester, elastomers, PET,thermoplastics, etc.).

Turning to FIG. 9, an oxygenated fluid delivery apparatus advantageouslyincludes a blood pump assembly 900; a first length of tubing 910 betweenthe pump assembly 900 and a blood oxygenation assembly 920; a secondlength of tubing 930 between the blood oxygenation assembly 920 and adelivery assembly 940; and the delivery assembly 940. As shown in FIG.9, the delivery assembly 940 includes a proximal portion 950, anintermediate portion 960, and a distal portion 970. Advantageously, thefluid delivery apparatus comprises a continuous fluid pathway betweenthe blood pump assembly 900 and the distal tip 980 of the deliveryassembly 940.

As shown in FIG. 9, the intermediate portion 960 may comprise arelatively short segment (e.g., about 1 cm in length) which necks downthe proximal portion 950 to meet the distal portion 970. In alternateembodiments, the intermediate portion may comprise a transition segmentof greater length including one or more portions joined end-to-end, eachportion including an inner fluid lumen through which oxygenated bloodmay flow. By varying the size, shape and materials of the variouscatheter portions and oxygenated blood fluid lumens, a catheter having adesired effective diameter, handling characteristics, etc. may beprovided for a particular desired application. Moreover, by varying thesize and length of the tube 930, and/or including flow restrictorsand/or other assemblies that affect the pressure drop along theoxygenated blood delivery pathway (e.g., a pressure cuff), a fluiddelivery apparatus (which in some cases may be characterized in terms ofan overall oxygenated blood fluid pathway effective diameter) may beprovided for achieving a desired range of oxygenated blood pO₂ for aparticular application.

By way of example, for an exemplary oxygenated blood fluid deliveryapparatus comprising a 1.4 m long catheter coupled at its proximal endto a 3 m oxygenated blood return tube having a 0.094 inch innerdiameter, oxygenated blood pressure at the oxygenation assembly 920 isplotted in FIG. 12 as a function of blood flow rate and cathetereffective diameter for an exemplary application involving the deliveryof oxygenated blood to a patient having a mean arterial pressure of 100mm Hg and a 38% hematocrit, and plotted in FIG. 13 as a functioneffective catheter inner diameter and hematocrit for an exemplaryapplication involving the delivery of oxygenated blood at 75 ml/min to apatient having a mean arterial pressure of 100 mm Hg. As shown in FIGS.12 and 13, for a constant blood flow rate Q_(blood), as the effectiveinner diameter of the catheter increases, the blood pressureP_(fluid(gauge)) at the oxygenation assembly 920 decreases.

By knowing the simplified and approximated bubble-free deliveryrelationship, ΔP_(fluid)>pO_(2(out)), a caregiver having a cathetercharacterized by effective inner diameter can use a chart such as FIG.12 to determine whether an appropriate range of blood flow rates areachievable if the caregiver were to use a fluid delivery apparatusincluding the catheter to deliver blood having a desired pO₂.Alternatively, a caregiver specifying a desired oxygenated blood pO₂ andoxygenated blood flow rate range can use a chart like the one shown inFIG. 12 as an aid to selecting a catheter for use in a fluid deliveryapparatus for a particular application. Similarly, other such charts(e.g., FIG. 13) may be used by the caregiver or others in otherapplications for assistance in providing an oxygenated blood fluiddelivery apparatus.

The present invention has been described in terms of exemplaryembodiments. In accordance with the present invention, the operatingparameters for the system may be varied, typically with a physician orcaregiver specifying and selecting them for the desired clinicalindication. Further, it is contemplated that other embodiments, whichmay be devised readily by persons of ordinary skill in the art based onthe teachings set forth herein, may be within the scope of the inventionwhich is defined by the appended claims. The present invention may bemodified and practiced in different but equivalent manners that will beapparent to those skilled in the art having the benefit of the teachingsset forth herein.

No limitations are intended to the details or construction or designshown herein, other than as described in the claims appended hereto.Thus, it should be clear that the specific embodiments disclosed abovemay be altered and modified, and that all such variations andmodifications are within the spirit and scope of the present inventionas set forth in the claims appended hereto.

What is claimed is:
 1. A device for oxygenating blood and delivering theoxygenated blood to a patient, the device comprising: a blood pumpassembly coupled to a supply of blood; a blood oxygenation assemblycoupled to the blood pump assembly, the blood oxygenation assemblyreceiving the blood from the blood pump assembly and oxygenating theblood, the blood oxygenation assembly comprising: a mixing chamberhaving a first inlet, a second inlet, and an outlet; a pump adapted todeliver the blood to the mixing chamber via the first inlet, wherein thefirst inlet is positioned on the mixing chamber in such a way that theblood enters the mixing chamber substantially tangential to a wall ofthe mixing chamber; and a gas-supersaturated fluid supply assemblyadapted to deliver an oxygen-supersaturated fluid having a liquid phasesupersaturated with oxygen to the mixing chamber via the second inlet tomix with the blood and form the oxygenated blood, wherein the oxygenatedblood exits the mixing chamber through the outlet; and a delivery systemcoupled to the blood oxygenation assembly, the delivery system beingadapted to deliver the oxygenated blood to a patient, the deliverysystem comprising: a generally tubular elongated member having aproximal end portion and a distal end portion, the proximal end portionbeing adapted to be inserted into the patient and the distal end portionbeing coupled to the blood oxygenation assembly, the member furtherhaving a first lumen for carrying the oxygenated blood generallyextending from the proximal end portion to the distal end portion, andthe member having a transition portion located between the proximal endportion and the distal end portion, the transitional portion beingrelatively flexible compared to the proximal end portion and beingrelatively stiff compared to the distal end portion.
 2. The device, asset forth in claim 1, comprising at least one hole located in aperipheral wall of the member and extending to the first lumen.
 3. Thedevice, as set forth in claim 2, wherein the at least one hole is formedin the distal end portion of the member.
 4. The device, as set forth inclaim 1, comprising a plurality of holes located in a peripheral wall ofthe member and extending to the first lumen.
 5. The device, as set forthin claim 4, wherein the plurality of holes are formed in the distal endportion of the member.
 6. The device, as set forth in claim 4, whereineach of the plurality of holes comprise a throughway axis, eachthroughway axis being generally perpendicular to a longitudinal axis ofthe member and being circumferentially offset from each adjacentthroughway axis.
 7. The device, as set forth in claim 1, comprising asecond lumen extending along at least a portion of the member.
 8. Thedevice, as set forth in claim 7, wherein the second lumen is sized andlocated to promote tracking of the member over a guidewire.
 9. Thedevice, as set forth in claim 1, comprising a radiopaque marker locatedon the member.
 10. A device for oxygenating blood and delivering theoxygenated blood to a patient, the device comprising: a blood pumpassembly coupled to a supply of blood; a blood oxygenation assemblycoupled to the blood pump assembly, the blood oxygenation assemblyreceiving the blood from the blood pump assembly and oxygenating theblood, the blood oxygenation assembly comprising: a mixing chamberhaving a first inlet, a second inlet, and an outlet; a pump adapted todeliver the blood to the mixing chamber via the first inlet, wherein thefirst inlet is positioned on the mixing chamber in such a way that theblood enters the mixing chamber substantially tangential to a wall ofdie mixing chamber; and a gas-supersaturated fluid supply assemblyadapted to deliver an oxygen-supersaturated fluid having a liquid phasesupersaturated with oxygen to the mixing chamber via the second inter tomix with the blood and form the oxygenated blood, wherein the oxygenatedblood exits the mixing chamber through the outlet; and a delivery systemcoupled to the blood oxygenation assembly, the delivery system beingadapted to deliver the oxygenated blood to a patient, the deliverysystem comprising: a generally tubular elongated member having aproximal end portion, a distal end portion, and a longitudinal axis, theproximal end portion being adapted to be inserted into the patient andthe distal end portion being coupled to the blood oxygenation assembly,the member further having a first lumen extending from the proximal endportion to the distal end portion for carrying the oxygenated blood, andhaving a plurality of holes formed in a peripheral wall of the memberand extending to the first lumen, the plurality of holes being locatedin the distal end portion of the member, each of the plurality of holeshaving a throughway axis, each throughway axis being generallyperpendicular to the longitudinal axis of the member and beingcircumferentially offset from each adjacent throughway axis.
 11. Thedevice, as set forth in claim 10, comprising a second lumen extendingalong at least a portion of the member.
 12. The device, as set forth inclaim 11, wherein the second lumen is sized and located to promotetracking of the member over a guidewire.
 13. The device, as set forth inclaim 10, comprising a radiopaque marker located on the member.
 14. Thedevice, as set forth in claim 10, wherein each throughway axis iscircumferentially offset from each adjacent throughway axis by 90degrees.
 15. The device, as set forth in claim 10, wherein the membercomprises a transition portion located between the proximal end portionand the distal end portion, the transitional portion being relativelyflexible compared to the proximal end portion and being relatively stiffcompared to the distal end portion.
 16. The device, as set forth inclaim 10, wherein the plurality of holes are spaced at least 0.5 inchesfrom a distal end of the member.
 17. The device, as set forth in claim10, wherein the plurality of holes are sequentially spaced along thelongitudinal axis.
 18. The device, as set forth in claim 10, wherein thefirst lumen terminates in an open distal end of the member.
 19. Thedevice, as set forth in claim 10, wherein the first lumen terminates ina closed distal end of the member.
 20. A device for oxygenating bloodand delivering the oxygenated blood to a patient, the device comprising:a blood pump assembly coupled to a supply of blood; a blood oxygenationassembly coupled to the blood pump assembly, the blood oxygenationassembly receiving the blood from the blood pump assembly andoxygenating the blood, the blood oxygenation assembly comprising: amixing chamber having a first inlet, a second inlet, and an outlet; apump adapted to deliver the blood to the mixing chamber via the firstinlet, wherein the first inlet is positioned on the mixing chamber insuch a way that the blood enters the mixing chamber substantiallytangential to a wall of the mixing chamber; and a gas-supersaturatedfluid supply assembly adapted to deliver an oxygen-supersaturated fluidhaving a liquid phase supersaturated with oxygen to the mixing chambervia the second inlet to mix with the blood and form the oxygenatedblood, wherein the oxygenated blood exits the mixing chamber through theoutlet; and a delivery system coupled to the blood oxygenation assembly,the delivery system being adapted to deliver the oxygenated blood to apatient, the delivery system comprising: a generally tubular elongatedmember having a proximal end portion, a distal end portion, and alongitudinal axis, the proximal end portion being adapted to be insertedinto the patient and the distal end portion being coupled to the bloodoxygenation assembly, the member further having a first lumen extendingfrom the proximal end portion to the distal end portion for carrying theoxygenated blood, and having a plurality of holes formed in a peripheralwall of the member and extending to the first lumen, the plurality ofholes being located in the distal end portion of the member, each of theplurality of holes having a throughway axis, each throughway axis beinggenerally perpendicular to the longitudinal axis of the member and beingcircumferentially offset from each adjacent throughway axis, the memberfurther having a transition portion located between the proximal endportion and the distal end portion, the transitional portion beingrelatively flexible compared to the proximal end portion and beingrelatively stiff compared to the distal end portion.
 21. The device ofclaim 1, 10, or 20, wherein the gas-supersaturated fluid supply assemblycomprises a fluid supply; a chamber having a first inlet, a secondinlet, a third inlet and an outlet; an oxygen gas supply coupled todeliver oxygen to the first inlet of the chamber; a piston assemblycoupled to receive fluid from the fluid supply and to deliver the fluidto the second inlet and the third inlet of the chamber; a nozzle coupledto the third inlet of the chamber, the nozzle delivering the fluid fromthe piston assembly to the chamber; a first valve coupled to the outletof the chamber, the first valve being coupled to an actuator assembly tocontrol delivery of oxygen-supersaturated fluid from the chamber, theoutlet of the chamber being coupled to the second inlet of the bloodoxygenation assembly to deliver the oxygen-supersaturated fluid intocontact with the blood to form the oxygenated blood; and a second valvecoupled to the second inlet, the second valve being coupled to anactuator assembly to control dilution during the creation ofoxygen-supersaturated fluid within the chamber.